title: Concurrent agonism of adenosine A2B and glucocorticoid receptors in human airway epithelial cells cooperatively induces genes with anti-inflammatory potential: a novel approach to treat chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A2B-receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57(kip2)), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A2B-receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.
authors.affiliation: Airways Inflammation Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Greer
authors.forename: Cara W
authors.initials: CW
authors.lastname: Page
authors.forename: Taruna
authors.initials: T
authors.lastname: Joshi
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000465:Algorithms; D000631:Aminopyridines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D010627:Phenethylamines / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
chemical_list: D058908:Adenosine A2 Receptor Agonists; D000631:Aminopyridines; C518875:BAY 60-6583; D010627:Phenethylamines; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D011965:Receptors, Glucocorticoid; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D051786:Cyclic AMP Response Element Modulator; D003907:Dexamethasone; D000242:Cyclic AMP; C026708:2-phenylaminoadenosine; D000241:Adenosine; D002118:Calcium